In cultures of human umbilical vein cells, capillary sprouts formed mainly where elongated cells abruptly lost their shared alignment, and fewer sprouts formed when researchers aligned the cells more uniformly
In cultures of human umbilical vein cells, capillary sprouts formed mainly where elongated cells abruptly lost their shared alignment, and fewer sprouts formed when researchers aligned the cells more uniformly
In a Science Advances article published on October 30, 2026, researchers grew a layer of these endothelial cells, which line the inside of blood vessels, on a collagen gel and added vascular endothelial growth factor VEGF. Sprouts formed mainly at the ends of “streams,” bundles of elongated cells.
A new capillary sprout is a strand of cells extending from the endothelial layer into the surrounding tissue. VEGF stimulates sprouting, but although the protein was supplied evenly across the cell layer, only about two sprouts per square millimeter formed over 66 hours. Which factors determine where sprouts form? According to the authors, studies have reported conflicting findings on the role of physical factors in sprouting, and “the underlying mechanisms remain largely unknown.”
Physicists describe a layer of elongated cells as a liquid crystal: the cells align in parallel, while the layer can flow. The cells actively pull on the gel beneath them. In this model, traction increases with sharper changes in cell orientation and elongation from one location to the next. In a 2017 study, canine kidney epithelial cells were pushed out of the layer at sites where alignment was disrupted. In a 2022 study, muscle cell precursors surrounding such sites could grow into twisted columns. The authors of the new study tested whether sprouts extend out of the plane of the layer at similar sites.
Only some cells elongated in response to VEGF, forming aligned streams among rounder neighbors. Sprouts formed mainly near “wedges”: the ends of streams, where elongated cells meet the stream boundary end-on and alignment breaks down most abruptly. The distances from 647 sprouts to the nearest wedge were generally shorter than the distances from randomly selected points within streams or regions of rounded cells to the nearest wedge. Thus, a wedge identifies a sprout location more precisely than the stream as a whole.
Calculations based on measured cell orientations predicted the greatest traction at the wedge. Measurements of force based on the displacement of beads embedded in the gel also showed a peak at that location.
Streams are maintained by a balance between two processes: microtubules, protein tubes inside the cell, elongate it, while contraction involving the proteins actin and myosin keeps it rounded. The drug nocodazole disrupts microtubules, causing cells to round up, but sprouts persisted. They were observed in depressions in the gel, often at the centers of vortices, where cells form rings around a single point. The authors concluded that wedges and vortices share a disruption of cell alignment.
If alignment determines where sprouts form, changing it should change the number of sprouts. The authors restricted cell attachment to strips 400, 200 and 100 micrometers wide, roughly the distances over which cells maintain a shared orientation. Narrower strips produced more uniform alignment along their length and fewer sprouts. The researchers repeated the test in a “microvessel-on-a-chip”: they lined a channel in collagen with the same cells and applied pressure to stretch its wall. The cells aligned around the circumference, and fewer sprouts formed than without pressure.
The authors identify geometric approaches to guiding blood vessel formation in laboratory-grown tissues as an area for further work. According to a 2019 review, a piece of such tissue without its own blood vessels receives oxygen solely by diffusion, which reaches a depth of about 100–200 micrometers. After transplantation, blood vessels from the host take approximately one to two weeks to grow throughout a 3-millimeter piece of tissue. Throughout that period, cells in its interior lack sufficient oxygen.